Medicinal Chemistry

Anxiety Disorders

湯鎧瑋助理教授

辦公室：N203-3
分機：2213
電子信箱：tangkw@[Link]
考試命題大綱暨參考用書
• Foye’s Principles of Medicinal Chemistry

授課教師
• 李冠漢教授、呂玉玲教授、湯鎧瑋助理教授（各1/3）

評分方式：
• 期中考
• 期末考
ANXI ETY DI SO RD ERS

• Psychoses: severe mental illnesses,

⚬ hallucinations and/or delusions
⚬ consensus reality is distorted or has disintegrated
• Anxiety disorders
⚬ the ability to comprehend reality is retained
⚬ cognition and mood problems can be disabling
• Anxiety
⚬ a sense of apprehensive expectation.
⚬ in reasonable amounts and at appropriate times, anxiety is helpful
⚬ too much anxiety can be deleterious
PSYCHO SES AND ANXI ETY DI SO RD ERS

• Anxiety considered pathological

⚬ completely inappropriate to the situation
￭ nocturnal panic attacks—episodes of extreme anxiety that arise out of the most
physiologically quiet times of the day, stage III/IV sleep
⚬ in excess of what the situation normally should call for
￭ an irrational fear of public spaces (agoraphobia)
• The estimates prevalence:
⚬ 18%/12% for specific phobia, 13%/7% for social phobia, 9%/2% for generalized
anxiety disorder
ANXI ETY DI SO RD ERS

• Include generalized anxiety disorder, separation anxiety disorder, social anxiety disorder
(social phobia), specific phobia, panic disorder, agoraphobia, and selective mutism
• Criteria of anxiety disorders
⚬ cannot be caused by an exogenous factor (e.g., caffeine) or a medical condition
(e.g., hyperthyroidism)
⚬ at least three (one in children) of the following symptoms must occur more days
than not for at least 6 months
￭ restlessness, irritability, muscle tension, difficulty to concentrate, sleep
disturbance, fatigue
ET IO LO GY O F ANXI ETY DI SO RD ERS

• The prefrontal cortex and limbic areas were thought to be involved in pathologic anxiety
• Genetic mechanisms underlying general symptoms of anxiety → unclear
• A significant comorbidity for anxiety and major depressive disorder in both children and
adults
⚬ suggesting mechanistic overlap between the disorders
⚬ neurotransmitters GABA, glutamate, norepinephrine, serotonin, and dopamine
involve in anxiety
ET IO LO GY O F ANXI ETY DI SO RD ERS

• Anxiety disorders are not simply a deficiency or excess of one neurotransmitter or

another
⚬ neurotransmitter systems have complex anatomical and functional
interrelationships
⚬ explain the unpredictable and sometimes paradoxical responses to medications
• Most drugs effective for anxiety disorders affect one or several of these
neurotransmitters
G ABA REC EPTORS

• GABA
⚬ γ-aminobutyric acid
⚬ major inhibitory neurotransmitter in the mammalian CNS
⚬ approximately one-third of all synapses uses for intercellular communication
• Two major classes of GABA receptors
⚬ inotropic GABAA receptor
⚬ metabotropic GABAB receptor
G ABA A REC EPTOR

• The GABAA receptor is a member of ligand-gated ion channels

⚬ conducts chloride to hyperpolarize the cell
⚬ decreases the firing probability of a neuron
• GABAA receptor distinct binding sites
⚬ GABA binding sites (orthosteric site)
￭ at the interface between α and β subunits
⚬ Neuroactive drugs binding sites (allosteric sites)
￭ at the α and γ subunits
￭ composition of α and γ determines the efficacy of benzodiazepines
￭ benzodiazepines, barbiturates, picrotoxin, ethanol, neurosteroids
G ABA A REC EPTOR
G ABA B REC EPTOR

• The GABAB receptor is a class-C GPCR

⚬ modulate activity of the effector proteins
⚬ adenylyl cyclase, G protein–activated inwardly rectifying K+ channels (GIRK)
channels, and G protein–dependent neuronal Ca2+ channels
• GABAB signaling include
⚬ hyperpolarization of neurons
⚬ inhibition of neurotransmitter release
• The GABAB GPCR exists as two major subtypes, GABA B(1) and GABAB(2)
⚬ GABAB(1) do not traffic to the cell membrane surface without GABA B(2)
⚬ they co-expresses on the cell surface to form a functional GPCR
G ABA B REC EPTOR

• GABAB receptors play a role in the pathophysiology and pharmacotherapy of a variety of

CNS diseases and disorders
⚬ Alzheimer’s disease, addiction (especially
ethanol), anxiety, autism spectrum disorder,
depression, epilepsy, Huntington’s disease,
pain, Parkinson’s disease, schizophrenia, and
stroke, as well as muscle spasticity disorders
and gastroesophageal reflux disease
BACLO FEN -G ABA B REC EPTOR AG O NI ST

• The only drug currently in clinical use that selectively interacts with the GABA B receptor
• Racemate: muscle relaxant and analgesic activity (chapter 10)
• R-(−)-enantiomer: stereoselectively interact (as an agonist) with GABAB receptor
• Off-label uses: to treat many other conditions thought to involve GABA B receptors,
including anxiety
• Therapeutic concentrations in brain are difficult to achieve
⚬ is transported out of the brain via the organic acid transporter
BACLO FEN -G ABA B REC EPTOR AG O NI ST

• Arbaclofen placarbil
⚬ prodrug of (R)-baclofen
⚬ developed to enhance oral absorption compared to the parent compound
⚬ studied to treat symptoms of autism and fragile X syndrome
⚬ not been approved
￭ convincing efficacy has not been established
DRU GS TARG ET ING G ABAA REC EPTORS FO R T HE T REAT ME NT O F
ANXI ETY

• Benzodiazepines
• Nonbenzodiazepine agonists at the Benzodiazepine Site (Z drugs)
⚬ cyclopyrrolone - eszopiclone
⚬ pyrazolopyrimidine - zaleplon
⚬ imidazopyridazine - zolpidem
BENZO DIAZEP INES

• The benzodiazepines are efficacious drugs for treating anxiety disorders

⚬ effectiveness and wide margin of safety
• A variety of benzodiazepines, each with minor differences
⚬ major factors to be considered
￭ include rate and extent of absorption, presence or absence of active
metabolites, and degree of lipophilicity
⚬ help to determine how a benzodiazepine is marketed and used
￭ rapidly absorbed and fast-acting → be used to treat panic attacks
DE VELO PM ENT O F BENZO DIAZ EP INE ANXI OLYTIC S

• In the 1950s, the medicinal chemist Sternbach at the New Jersey laboratories of
Hoffman LaRoche
❑ Synthesis: chloromethylquinazoline N-oxides with
amines
❑ Predict: “tranquilizer”(anxiolytic) activity
❑ Yield: unexpected rearrangement
✓ 7-chloro-2-(N-methylamino)-5-phenyl-3H-1, 4,-
benzodiazepin-4-oxide was found
❑ Results: hypnotic and sedative properties
• Market: chlordiazepoxide, in 1960, anxiolytic agent
DE VELO PM ENT O F BENZO DIAZ EP INE ANXI OLYTIC S

• Enhance its “pharmaceutical elegance”

⚬ structural modifications
⚬ led to the diazepam in 1959
❑ contains no basic nitrogen moiety
❑ 3- to 10-fold more potent
❑ marketed in 1963 as the anxiolytic
drug Valium
• Subsequently, thousands of benzodiazepine
derivatives...
DE VELO PM ENT O F BENZO DIAZ EP INE ANXI OLYTIC S

• Major advance in 1981

⚬ Flumazenil, imidazobenzodiazepinone derivative, was first reported
⚬ high affinity to the benzodiazepine binding site
⚬ blocks the pharmacological effects of the classical benzodiazepines
⚬ binding is not affected by GABA and has no intrinsic activity
⚬ a neutral antagonist, clinically used to reverse benzodiazepine-induced sedation in
overdose
M ECH AN ISM OF ACTI ON OF AN XI OLYTIC BE NZOD IAZE P IN ES

• Positive allosteric modulators (PAMs) of GABA binding to GABA A

⚬ anxiolytic benzodiazepines
⚬ not directly alter transmembrane chloride conduction to produce their anxiolytic
effects
⚬ when an anxiolytic benzodiazepine binds to the benzodiazepine site
⚬ greatly increases the affinity of GABA at GABAA
⚬ leads to a strong potentiation of chloride conductance
⚬ increase in cell hyperpolarization (e.g., decreases activity of a neuron)
M ECH AN ISM OF ACTI ON OF AN XI OLYTIC BE NZOD IAZE P IN ES

• Neutral antagonists benzodiazepines, such as flumazenil

⚬ bind to the benzodiazepine site
⚬ have no effect on the intrinsic activity of the GABAA receptor
⚬ block access of other drugs (e.g., PAMs and negative allosteric modulators)
• Negative allosteric modulators (or inverse agonists), such as RO 15-4513
⚬ bind to the benzodiazepine site
⚬ decrease GABA binding
⚬ decreases chloride conductance through the channel
⚬ leading to cell depolarization (e.g., increases activity of a neuron)
M ECH AN ISM OF ACTI ON OF AN XI OLYTIC BE NZOD IAZE P IN ES
M ECH AN ISM OF ACTI ON OF AN XI OLYTIC BE NZOD IAZE P IN ES

• Different α and γ subunit compositions give rise to subtypes of the GABAA

⚬ pharmacologically distinct with regard to ligand affinity and intrinsic activity
⚬ providing a mechanistic basis anxioselective ligand (i.e., anxiolysis in the absence of
sedation, muscle relaxation, amnesia, and ataxia)
⚬ GABAA α2,3, and 5 subunits mediate anxiolytic and muscle relaxant effects
⚬ GABAA α1 subunits mediate the sedative effects
• Currently used benzodiazepines are not selective for particular α subtypes
⚬ several putative anxioselective benzodiazepines are still in clinical trial
ST RU CT URE -ACT IVI TY RELATIO NSHI PS

• Ring A
⚬ the minimum requirement for binding to the benzodiazepine site
⚬ aromatic or heteroaromatic ring
⚬ π-π stacking with aromatic amino acid residues of the receptor
• Substituents on ring A
⚬ 7-position with electronegative group (e.g., halogen or nitro)
￭ markedly increases functional anxiolytic activity
⚬ 6, 8, or 9-positions’ substituents
￭ generally decrease anxiolytic activity
• Ring A is replaced by a heterocycle
⚬ generally show weak binding affinity (compared to phenyl)
ST RU CT URE -ACT IVI TY RELATIO NSHI PS

• Ring B
⚬ a proton-accepting group is structurally required
￭ for interactions with a histidine residue
￭ serves as a proton source in the GABAA α1 subunit

⚬ the carbonyl moiety in the 2-position of ring B optimize affinity

￭ form a coplanar spatial orientation with the aromatic ring A
￭ Substitution of sulfur may affect selectivity for binding to GABA receptors
￭ anxiolytic activity is maintained
ST RU CT URE -ACT IVI TY RELATIO NSHI PS

• Ring B
⚬ Substitution of the methylene 3-position or the imine nitrogen
￭ sterically unfavorable for antagonist activity
￭ no effect on PAM (i.e., anxiolytic) activity
⚬ 3-hydroxy substituted derivatives
￭ have comparable potency to nonhydroxylated analogues
￭ excreted faster
⚬ Esterification of a 3-hydroxy moiety
￭ also have comparable potency
ST RU CT URE -ACT IVI TY RELATIO NSHI PS

• Ring B
⚬ Neither the 1-position amide nitrogen nor its substituent is required for in vitro
￭ relatively long N-alkyl side chains do not dramatically decrease affinity
￭ sterically large substituents like tert-butyl drastically reduce receptor affinity and in vivo
activity
⚬ Neither the 4,5-double bond nor the 4-position nitrogen (the
4,5-[methyleneimino] group) is required for in vivo anxiolytic
activity
￭ proposed that in vivo activity results from oxidation back to
C=N
ST RU CT URE -ACT IVI TY RELATIO NSHI PS

• Ring C
⚬ not required for binding to the benzodiazepine site in vitro
￭ may contribute favorable hydrophobic or steric interactions to receptor
￭ relationship to ring A planarity may be important
⚬ Substitution at the 4′-position
￭ unfavorable for PAM activity
⚬ Substitution at the 2′-position
￭ not detrimental
⚬ suggesting that limitations at the p-position are steric, rather
than electronic
ST RU CT URE -ACT IVI TY RELATIO NSHI PS

• 1,2-Annulation
⚬ Annelating with an additional “electron-rich” ring
￭ such as triazole or imidazole
￭ results in pharmacologically high affinity for the benzodiazepine site
￭ lead to clinically effective anxiolytic agents
⚬ S-triazolo-benzodiazepines
￭ triazolam, alprazolam, and estazolam
⚬ imidazo-benzodiazepine
￭ midazolam
ST EREO CHE MIST RY

• Most clinically useful benzodiazepines

⚬ do not have a chiral center
⚬ the seven-membered ring B may adopt two possible boat
conformations
⚬ they are “enantiomeric” (mirror images) to each other
⚬ two conformations can easily interconvert at room
temperature
⚬ it impossible to predict which conformation is active
ST EREO CHE MIST RY

• Introducing a 3-substituent
⚬ provide a chiral center and enantiomeric pairs of derivatives
￭ S-enantiomer of 3-methyldiazepam stabilizes conformation A
￭ R-enantiomer of 3-methyldiazepam stabilizes conformation B
• In vitro and in vivo anxiolytic activity of 3-methylated enantiomers were found to reside
in the S-isomer
⚬ conformation A would be the active form
• The commonly used 3-hydroxylated derivatives (e.g., lorazepam and oxazepam) are
commercially available only as racemic mixtures
PH YSIO CH EMIC AL AND PH ARMACOKINE TIC S

• In general
⚬ most benzodiazepines have relatively high Log P values
￭ Log P values: lipid/water partition coefficients
⚬ completely absorbed after oral administration
⚬ rapidly distributed to the brain and other highly perfused organs
• A notable exception: clorazepate
⚬ firstly, rapidly decarboxylated at the 3-position to N-desmethyldiazepam
⚬ subsequently, quickly absorbed
• Overall, chlorazepate clinical and pharmacokinetic properties are similar to
chlordiazepoxide and diazepam
PH YSIO CH EMIC AL AND PH ARMACOKINE TIC S

• Most benzodiazepines and their metabolites bind to plasma proteins

⚬ binding degree: dependent on lipophilicity of the compound
￭ more polar benzodiazepines: approximately 70%, such as alprazolam
￭ very lipophilic benzodiazepines: 99%, such as diazepam
• The major metabolic disposition of most benzodiazepines
⚬ hepatic microsomal oxidation
￭ including N-dealkylation and aliphatic hydroxylation
￭ by a wide variety of CYP enzymes
• Subsequent conjugation by glucuronyl transferases yields polar glucuronides that are
excreted in urine
CH LORD IAZEPOX IDE

• Hepatic metabolism is mainly by CYP3A4

⚬ giving the initial N-desmethylation product, N-desmethylchloridiazepoxide
⚬ subsequently deaminated to form the demoxepam
• Demoxepam is extensively metabolized,
⚬ undergo four different metabolic fates
a. Removal of the N-oxide moiety yields the active metabolite, N-desmethyldiazepam
(desoxydemoxepam)
￭ a metabolite of both chlordiazepoxide and diazepam
￭ be hydroxylated to yield oxazepam
CH LORD IAZEPOX IDE

a. hydrolysis to the “opened lactam,” which is inactive

b. The two other metabolites of demoxepam
￭ ring A hydroxylation (9-hydroxydemoxepam)
￭ ring C hydroxylation (4′-hydroxydemoxepam)
￭ both of which are inactive
• The major metabolic glucuronide: oxazepam and other phenolic (9- or 4′-hydroxylated)
metabolites
• Repeated administration of chlordiazepoxide
⚬ result in accumulation of parent drug and its active metabolites
⚬ may have excessive sedation
CH LORD IAZEPOX IDE
DI AZE PAM
• Diazepam is rapidly and completely absorbed after oral administration
⚬ half-life of approximately 20-50 hours
• Hepatic metabolism is mainly by CYP3A4
⚬ The major, active metabolic product: N-desmethyldiazepam
⚬ Hydroxylation of N-desmethyldiazepam at the 3-position gives the active metabolite
oxazepam
• Repeated administration of diazepam or chlordiazepoxide
⚬ accumulation of N-desmethyldiazepam
⚬ can be detected in the blood for more than 1 week after discontinuation
OXAZEPAM
• An active metabolite of both chlordiazepoxide and diazepam
• Marketed as a short-acting anxiolytic agent
⚬ rapidly inactivated to glucuronidated metabolites
⚬ half-life of oxazepam is approximately 4-8 hours
• Cumulative effects: much less than with long-acting benzodiazepines
• Lorazepam: 2′-chloro derivative of oxazepam
⚬ similarly short half-life (2-6 hr) and pharmacological activity
MI DAZO LAM
• Midazolam has a pKa of 6.2
⚬ highly water soluble (pH <4)
⚬ highly lipid soluble (pH >4)
• The most commonly used benzodiazepine as a premedication for anesthesia
⚬ quick onset (1-2 min) and recovery (20 min) after a bolus injection
⚬ longer time to full altertness (40 minutes, > propofol (10 min))
• The intravenously administered preparation - dihydrochloride salt
⚬ buffered to pH 3
⚬ acid-catalyzed diazepine ring open at the 4,5-double bond
⚬ assists water solubility but renders the compound inactive
MI DAZO LAM

• The dihydrochloride salt preparation consists of

⚬ 80%-85% of the ring-opened structure
⚬ 15%-20% of the ring-closed form
⚬ completely reforms to the active midazolam at pH 7.4
• Hepatic metabolism mainly by CYP3A4 and CYP3A5
⚬ yield hydroxylated derivatives
⚬ do not contribute to pharmacological activity at usual doses
⚬ subsequently excreted as glucuronide conjugates
PH ARMACOKINE TIC S O F BENZO DIAZ EP INES

• Detailed pharmacokinetic analysis for most benzodiazepines is complex

⚬ lipophilic drugs is further complicated by enterohepatic circulation
⚬ the distributive (α) half-life of diazepam is approximately 1 hour
⚬ the elimination (β) half-life is approximately 1.5 days, acutely
• Plasma concentration and clinical effectiveness of benzodiazepines is difficult to
correlate
⚬ only a twofold increase in effective levels produces sedative side effects
⚬ not safe or effective when given in once-daily dose
⚬ usually are divided into two to four doses per day for treatment of daytime anxiety
DRU GS TARG ET ING G ABAA REC EPTORS FO R T HE T REAT ME NT O F
ANXI ETY

• Benzodiazepines
• Nonbenzodiazepine Agonists at the Benzodiazepine Site (Z drugs)
⚬ cyclopyrrolone - eszopiclone
⚬ pyrazolopyrimidine - zaleplon
⚬ imidazopyridazine - zolpidem
⚬ show greater selectivity for GABAA receptors containing the α1 subunit
ZO PIC LONE

• Structure: cyclopyrrolones
• “superagonist” of the benzodiazepine site
⚬ especially the subunit composition α1 β2 γ2 and α1 β2 γ3
• Racemic: zopiclone, available in Europe since 1992
• S-enantiomer: eszopiclone, higher-affinity, available in the US since 2005
• used primarily to treat insomnia
⚬ rapid onset and moderate duration (half-life, ∼6 hr) of hypnotic effect
• Extensive CYP3A4- and CYP2E1-catalyzed oxidation and demethylation
⚬ metabolites excreted primarily in urine
ZA LEPLON

• Structure: pyrazolopyrimidine
• Selective high affinity for α1-containing benzodiazepine sites
• used primarily to treat insomnia
⚬ decrease sleep latency
⚬ does not appear to induce withdrawal symptoms or rebound insomnia
⚬ absorbed rapidly, half-life approximately 1 hour
• Metabolism:
⚬ oxidized by aldehyde dehydrogenase and CYP3A4 to inactive metabolites
⚬ converted to glucuronides and eliminated in urine
ZO LPID EM

• Structure: imidazopyridines
• α1 subunit-selective ligands of the benzodiazepine
• Available as a sedative-hypnotic in the US in 1993
⚬ shortening sleep latency
⚬ prolonging total sleep time
⚬ without affecting sleep stages
⚬ readily absorbed from the gastrointestinal tract
⚬ half-life of approximately 2 hours
• Extensively metabolized by the liver to inactive oxidized products
Thank you!